The Conformational Wave in Capsaicin Activation of Transient Receptor Potential Vanilloid 1 Ion Channel

Fan Yang,Xian Xiao,Bo Hyun Lee,Simon Vu,Wei Yang,Vladimir Yarov-Yarovoy,Jie Zheng

doi:10.1016/j.bpj.2018.11.2439

Fan Yang, Xian Xiao + Show 5 more

Open Access

https://doi.org/10.1016/j.bpj.2018.11.2439

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Abstract

The capsaicin receptor TRPV1 has been intensively studied by cryo-electron microscopy and functional tests. However, though the apo and capsaicin-bound structural models are available, the dynamic process of capsaicin activation remains intangible, largely due to the lack of a capsaicin-induced open structural model and the low occupancy of the transition states. Here we report that reducing temperature toward the freezing point substantially increased channel closure events even in the presence of saturating capsaicin. We further used a combination of fluorescent unnatural amino acid (fUAA) incorporation, computational modeling, and rate-equilibrium linear free-energy relationships analysis (Phi-analysis) to derive the fully open capsaicin-bound state model, and reveal how the channel transits from the apo to the open state. We observed that capsaicin initiates a conformational wave that propagates through the S4-S5 linker towards the S6 bundle and finally reaching the selectivity filter. Our study provides a temporal mechanism for capsaicin activation of TRPV1.

Highlights

2239-Plat Gain-Of-Function Mutationsin TRP melastatin 4 (TRPM4) Activation Gate Cause Skin Disease progressive symmetric erythrokeratoderma (PSEK) Huijun Wang1, Zhe Xu2, Bo Hyun Lee3, Simon Vu3, Linghan Hu1, Mingyang Lee1, Dingfang Bu1, Xu Cao1, Samuel Hwang4, Yong Yang1, Jie Zheng3, Zhimiao Lin1. 1Dept Dermatology, Peking University First Hospital, Beijing, China, 2Dept
The slopes of the mean square angular displacement (MSD) curves obtained from TRPV1 were shifted upward in response to capsaicin, which reflects Diffracted X-ray Tracking (DXT) successfully extracted the internal motion of TRPV1
We observed that capsaicin initiates a conformational wave that propagates through the S4-S5 linker towards the S6 bundle and reaching the selectivity filter

Summary

Introduction

2239-Plat Gain-Of-Function Mutationsin TRPM4 Activation Gate Cause Skin Disease PSEK Huijun Wang1, Zhe Xu2, Bo Hyun Lee3, Simon Vu3, Linghan Hu1, Mingyang Lee1, Dingfang Bu1, Xu Cao1, Samuel Hwang4, Yong Yang1, Jie Zheng3, Zhimiao Lin1. 1Dept Dermatology, Peking University First Hospital, Beijing, China, 2Dept. Intracellular calcium exert a negative control over the activity of these channels. Molecular dynamics simulations suggest that the inactivation phenotype can be explained by specific conformational changes induced by calcium coordination to a structural triad formed by the HLH domain, the intracellular connector between TM S2-S3, and the TRP helix. The TRPV1 is a nonselective cation channel that responds to various signals including capsaicin, heat, and low pH condition.

Results

Conclusion